Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer
| Autor: | Anil K. Sood, Yiling Lu, Mihai Gagea, Jinsong Liu, John E. Ladbury, Guillermo N. Armaiz Pena, Gordon B. Mills, Charles V. Kingsley, Mikhail Bogdanov, Yong Zhou, Cristina Ivan, Courtney Vallien, Zamal Ahmed, Andrew B. Gladden, Mien Chie Hung, John F. Hancock, Xin Hu, Zahra Timsah, Gabriel Lopez-Berestein, Jonathan Berrout |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinogenesis medicine.medical_treatment Phosphatidylinositols Article Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences Genetics medicine Animals Humans PTEN Receptor Fibroblast Growth Factor Type 2 Molecular Biology Protein kinase B Cell Proliferation GRB2 Adaptor Protein Ovarian Neoplasms biology Phospholipase C gamma Fibroblast growth factor receptor 2 Growth factor PTEN Phosphohydrolase Signal transducing adaptor protein Prognosis Cell biology Gene Expression Regulation Neoplastic Oncogene Protein v-akt 030104 developmental biology Tumor progression biology.protein Cancer research Female GRB2 Signal transduction Signal Transduction |
| ISSN: | 0950-9232 |
| Popis: | In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink